We propose a new CSER site, NYCKidSeq, to advance the implementation of genomic medicine in children from underrepresented minority populations in Harlem and the Bronx. We will address three key challenges associated with implementing genomics for low income and diverse populations; diversity, communication and community engagement. NYC, particularly Harlem and the Bronx, has the most diverse population in the United States, yet children from these communities bear a disproportionate burden of illness and lack of access to quality care, and lag in benefitting from advances in research and technology. We will therefore perform whole genome sequencing (WGS) for diagnostic purposes in 1200 children from ancestrally and socioeconomically diverse backgrounds who have undiagnosed neurologic, cardiac, or immune disorders. We will evaluate the individual clinical utility of WGS and the impact on healthcare costs, and compare its diagnostic accuracy to targeted gene panels and chromosomal microarray. Given the complexity of genomic interpretation, open, broadly targeted, and comprehensive communication is essential. To address this, we will first evaluate participants' understanding and attitudes about genomic testing and decision-making, and will then incorporate these findings into the development of a suite of software resources to facilitate web-based exploration of the results of genetic testing, enhance education and counseling about genomic medicine, and communication to carers at all levels of expertise. Recognizing that poor communication and issues with understanding and translating the new ?language? of genomic sequencing are major barriers to implementation, we will address this at three levels of community engagement: primary care providers, communities, and participating parents in order to create dialogue and facilitate understanding and transparency. This powerful collaboration between the Mount Sinai Health System, Albert Einstein College of Medicine/Montefiore Medical Center, and the New York Genome Center presents a unique ?real life? opportunity to mutually build upon strengths while addressing implementation challenges across health care systems. Overall, this work will inform the global genomics and clinical communities about how to implement genomic medicine in a diverse population in a clinically useful, technologically savvy, culturally sensitive, and ethically sound manner.